Project Summary/Abstract Despite therapeutic advances, no current treatment fully reverses impaired heart function. Heart failure often develops in individuals with coronary artery disease; high blood pressure or have suffered a myocardial infarction. Heart failure can develop at any age, but increases in prevalence with age. Moreover, individuals of advanced age also develop a syndrome of heart failure with preserved ejection fraction (HFpEF). Experimental models of aging as well as human studies suggest that endogenous repair capabilities become depleted with age. Therefore, novel interventions that preserve cardiac homeostasis are essential to reduce heart failure associated morbidity and mortality. Our novel and potent family of synthetic peptide analogues of Growth Hormone Releasing Hormone (GHRH) receptor agonists (GHRH-As) produce a comprehensive repair program in two models of heart failure associated with ischemic heart disease. Treatment with GHRH-A improved cardiac function and attenuated remodeling in both acute and chronic models of ischemic injury, and improved peripheral vascular function. These effects are mediated by direct activation of GHRH receptor signaling, promoting endogenous cell survival and repair mechanisms. However, the cellular targets and mechanisms involved remain to be elucidated. The long-term goal of this proposal is to identify the mechanisms underlying GHRH- mediated cardiac protection and apply GHRH-targeted therapeutics to prevent HFpEF. We propose a combination of in vivo and ex vivo approaches to test the central hypothesis that activation of GHRHR signaling restores cardiac structure and function in HFpEF by promoting cardiomyocyte proliferation and reducing fibrosis and apoptosis. The specific aims of this grant are to test the hypotheses that 1) GHRH Receptor signaling regulates cardiomyocyte function; 2) GHRH-A therapy prevents cardiovascular changes and/or restores cardiovascular function in Ang II-induced mouse models of HFpEF; and 3) GHRH-As prevent and/or reverse HFpEF in a porcine model of chronic kidney disease. Together this series of aims will provide novel insights into the mechanisms by which GHRH-As are cardioprotective and to the development of novel and effective therapeutic approaches tailored to improve cardiac performance in patients with HFpEF and other cardiovascular diseases.